ETP-ALL (early T-cell precursor acute lymphoblastic leukemia) is a high-risk subtype of early T-cell leukemia. The distinctive immunophenotype of ETP-ALL is characterized by CD1a-, CD8-, CD5-, or weak-positive <75%. The complex karyotype and genomic instability are well-known characteristics of ETP-ALL. Throughout all disease stages, we examined the karyotypes, protein expressions, immunophenotypes, and gene expression profiles. The relapse's karyotype analysis reveals new mutations not found during diagnosis, some of which are unprecedented in any ETP-ALL case reported in the literature. Alterations are present in chromosomes 4, 6, 16, and 18 (BCL-2 locus). Immunophenotype analysis shows drastic changes from diagnosis to relapse in ETP-ALL, including CD56 switch and unusual CD5 and CD8 switches. After comparing the patient's relapse-stage marrow with the healthy subject's control marrow and the non-ETP ALL subject at the same stage, protein analysis showed the IL23R-SGK1-RANBP1 asset is overexpressed, along with MARCH5 and BLC-2. Additionally, the expression of BIM, a negative regulator of BCL-2, decreases, as well as Mitofusin-2 (MFN2), which plays a role in mitochondrial fusion and network maintenance. A test conducted on ex vivo blasts confirms that Venetoclax is sensitive at different levels during the relapse phase but not in the early stages. This confirms that disease-related genetic changes led to blast expansion, dependent on BCL2, and is associated with the feedback regulation of transcript expression. Throughout the disease progression, we examined bone marrow and peripheral blood smears. These prove the failures of all therapeutic lines and HSCT, as well as the knockdown of leukemic blasts and the resumption of bone marrow activity (measured by neutrophil levels) with venetoclax administration. In summary, ourunderstanding of the BCL2 pathway's impact in ETP-ALL is limited, and the occasional use of venetoclax is not yet standardized in guidelines. Our results highlight the importance of assessing BCL2 expression in refractory ETP-ALL cases.